Non-type 2 airway inflammation in severe asthma: from bench to bedside

Severe asthma remains a major clinical challenge despite substantial advances in biologic therapies targeting type 2 inflammation. Whereas type 2-high asthma is increasingly well characterized and effectively treated, a considerable proportion of patients exhibit type 2-low and non-type 2 inflammatory phenotypes, which are frequently associated with neutrophilic airway inflammation, corticosteroid insensitivity, poor symptom control, and persistent disease burden. However, the biological mechanisms underlying these phenotypes remain incompletely understood, and effective targeted therapies are limited. In this review, current evidence regarding the clinical characteristics, pathogenic mechanisms, and emerging therapeutic targets associated with non-type 2 airway inflammation including non-allergic, non-eosinophilic and type 2-low asthma is summarized. Clinical studies indicate that obesity, exposure to air pollutants, cigarette smoking, and respiratory viral infections are important contributors to these inflammatory phenotypes and are often associated with increased disease severity and reduced responsiveness to corticosteroids. Mechanistically, activation of innate and adaptive immune pathways involving interleukin (IL)-17A, IL-6, thymic stromal lymphopoietin (TSLP), and osteopontin promotes neutrophilic airway inflammation and airway hyperresponsiveness. Recent findings also highlight the importance of the gut-lung axis, suggesting that alterations in the gut microbiome and its metabolites contribute to systemic and airway inflammation, particularly in obesity-associated asthma. Although several candidate therapeutic targets have emerged, including IL-17A, TSLP, osteopontin, IL-6, and microbiome-related pathways, clinical translation has been challenging, and reliable biomarkers for patient stratification remain lacking. The substantial biological heterogeneity of non-type 2 inflammatory phenotypes further complicate disease classification and therapeutic development. A better understanding of the interactions among environmental exposures, metabolic factors, and immune responses will be essential for refining asthma endotypes and advancing precision medicine approaches for patients with severe asthma characterized by non-type 2 airway inflammation.